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G Mazue

Publications and source records attributed to G Mazue.

15 recordsLinked to original sources
PubMed1994

Urinary bladder hyperplasia in the rat: non-specific pathogenetic considerations using a beta-lactam antibiotic.

Eight of the known chemical substances associated with neoplasia in man are known to target the urinary bladder urothelium. Preneoplastic changes have been identified following exposure to each of these chemicals, and they have also been seen to occur in many species of lab animals. The most important such change is preneoplastic hyperplasia. Adaptive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves disruption of homeostasis. Its severity increases with dose and time. It is not seen in controls but it is still reversible during the recovery segment after exposure to a toxic substance. When reparative hyperplasia continues beyond a certain threshold of time and dose, it progresses to preneoplastic hyperplasia, which further progresses with continued stimulation to frank neoplasia. The synthetic beta-lactam penem antibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive urothelial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 22101, it can be deduced that the morphologic finding of adaptive urothelial hyperplasia is caused by reduction of intravesicular urine pH. This effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in preclinical toxicity studies.

Animals↗
PubMed1985

Intestinal pathology in the dog induced by sublethal doses of amiodarone.

Amiodarone (A), an unique antiarrhythmic agent and amphiphilic drug, induces at sublethal doses dyslipidic storage in animals. The present work demonstrates a distinct intestinal pathology or "Malabsorption Syndrome" in the dog induced by A. Signs of intestinal pathology were observed in all animals receiving 100 mg/kg, but not in those receiving less than 50 mg/kg, after one month. The malabsorption syndrome was demonstrated by a dynamic study of lipid absorption and pathological lesions (partial villous atrophy and the accumulation of macrophages with dyslipidic inclusions.

Amiodarone↗
PubMed1985

Haemodynamic effects of the renin inhibitor SR 42128 in conscious baboons.

We studied the haemodynamic effects of captopril [3 mg/kg intravenously (i.v.)] and SR 42128 (8 mg/kg in a 30-min perfusion) in the conscious baboon after sodium depletion by furosemide. The evolution of the following parameters was studied: plasma renin activity (PRA), heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), first derivative of the left intraventricular pressure (dP/dt) and total peripheral resistance (TPR). Captopril (n = 5) increased PRA twofold and decreased MAP and TPR. Heart rate, CO and dP/dtmax were not significantly modified. As compared with a control group (n = 5), SR 42128 (n = 5) decreased PRA to almost undetectable levels for at least 2 h and decreased MAP, CO and TPR. It did not alter HR or dP/dtmax. Thus we can conclude that SR 42128 is a long-acting inhibitor of circulating renin in baboons and, in our experimental conditions, SR 42128, like captopril, induced a decrease in blood pressure without detrimental effect on cardiac function.

Animals↗
PubMed1984

Lack of initiating or promoting activity of six benzodiazepine tranquilizers in rat liver limited bioassays monitored by histopathology and assay of liver and plasma enzymes.

Six benzodiazepine tranquilizers were tested in limited in vivo bioassays for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. The benzodiazepine produced no liver altered hepatocellular foci during a 14-week period of administration whereas a large number were produced by the liver carcinogen, N-2-fluorenylacetamide. To assay for promoting activity and confirm the lack of initiating activity, N-2-fluorenylacetamide was used to produce altered foci and early neoplastic nodules in rat liver by 8 weeks of dietary administration and the benzodiazepines were then administered for 12 weeks. The liver neoplasm promoter phenobarbital had a substantial enhancing effect upon the persistence of early lesions but none of the benzodiazepines showed a similar effect. Thus in these limited bioassays monitored by histopathology, the benzodiazepine tranquilizers failed to exhibit either an initiating or a promoting action. In these studies, the liver and plasma enzymes, glutamate-pyruvate transaminase, glutamate-oxalacetic transaminase, lactic dehydrogenase, alkaline phosphatases, and gamma-glutamyltranspeptidase were monitored to determine if any alterations correlated with liver pathological changes. gamma-Glutamyltranspeptidase activity in both liver and plasma was markedly increased during initiation by N-2-fluorenylacetamide. Following cessation of carcinogen exposure, gamma-glutamyltranspeptidase remained elevated, providing an indication of past initiation. Administration of phenobarbital after N-2-fluorenylacetamide resulted in an elevation of liver and plasma gamma-glutamyltranspeptidase, but none of the benzodiazepines produced this effect and thus no biochemical evidence of a promoting effect on the liver was observed. Correlations between liver and plasma gamma-glutamyltranspeptidase and the occurrence of foci were excellent, indicating that determination of plasma activity can be used as an index of the process of hepatocarcinogenesis.

2-Acetylaminofluorene↗
PubMed1984

Recovery from amiodarone-induced lipidosis in laboratory animals: a toxicological study.

Numerous amphiphilic cationic drugs cause lipid-lysosomal storage in animal tissues; one of these drugs is amiodarone, a major antiarrhythmic agent. The toxicological effects of amiodarone were studied in three animal species (rats, dogs, and monkeys). It was shown that sublethal dose levels of amiodarone induced lipid storage in a great variety of tissues in rats (Fischer and Sprague-Dawley strains) and dogs. However, this change was not observed in baboons and Wistar rats. This storage, essentially characterized by lamellated inclusions, affected foamy macrophages, and at a later phase multiple cell types. Tissue biochemical analysis provided evidence of the phospholipidic nature of the storage. In addition, amiodarone induced an increased cholesterolemia and marked modifications of the lipoproteinogram. The kinetics of lipid storage was demonstrated following oral administration of amiodarone. After jejunal absorption, lipid storage occurred in the mesenteric lymph nodes followed by widespread deposition in the other lymph nodes and tissues, particularly in the lung. A complete recovery from lipid storage as observed in dogs and rats. Finally, an investigation of a correlation between animal and man by means of long-term experiments is proposed.

Amiodarone↗
PubMed1984

Oxetorone-induced hyperprogesteronemia and the development of uterine decidual lesions in rats.

Application of the deciduoma formation test showed that 3-benzofurol[3,2-c][1] benzoxepin-6(12H)-ylidene-N,N-dimethyl-l-propanamin-(E )-2-butenedioate (1:1) (oxetorone, L-6257, Nocertone) stimulated secretion of progesterone by the ovaries in rats and that this hyperprogesteronemia resulted from an increased secretion of prolactin. The studies carried out also showed that the apparition of uterine decidual lesions observed in certain animals undergoing chronic oxetorone treatment was linked to this hyperprogesteronemia. In view of the specific physiology of prolactin in rodents, such uterine lesions can only develop in these animals and cannot occur in man.

Animals↗
PubMed1983

[Cancerogenic activity of antimitotic agents in animals].

In past years, health authorities have exempted anti-neoplastic agents from undergoing carcinogenesis tests. However, in view of increasing knowledge of this therapeutic family and of patients' increased life expectancy, toxicologists are having to reconsider the problem from both ethical and scientific points of view. Analysis of data has established a correlation between mutagenic activity of these molecules, carcinogenic activity in the animal and carcinogenic activity in man. For this reason, studies in laboratory animals are of interest at the present time. Assessment of the carcinogenic activity of anti-neoplastic agents in animals must take into account the chemical structure of the drug. The experiments to be carried out are: either in vitro, short term tests aimed to detect genotoxic drugs by mutagenesis tests, or limited in vivo tests, in order to determine the promoting or initiating character of these drugs. However, the obtention of negative results with the latter tests does not exclude the necessity of long term tests. Whatever the results obtained during these experiments, the decision to stop or to continue the development of an anti-neoplastic agent does not belong exclusively to the toxicologist, who can assess the risk, but not the potential benefice.

Animals↗
PubMed1982

Drug immunotoxicological approaches with some selected medical products: cyclophosphamide, methylprednisolone, betamethasone, cefoxitine, minor tranquillizers.

Alterations of the normal immune response were estimated in C57B1/6 mice pretreated with cyclophosphamide, methylprednisolone sodium succinate, betamethasone sodium phosphate or cefoxitine as positive controls and three minor tranquillizers: dipotassium chlorazepate, diazepam and meprobamate. The specific immune response against sheep red blood cells (SRBC) was evaluated by numeration of the direct plaque-forming cells (PFC; humoral immunity) and by measurement of the footpad swelling (delayed-type hypersensitivity, DTH). In our experiments, the results with the positive controls were in the same order as those described by others, and at the dose levels used, these three minor tranquillizers did not really alter the specific humoral and cellular immune response against SRBC in the C57B1/6 mice.

Animals↗
PubMed1982

Limited in vivo bioassays on some benzodiazepines: lack of experimental initiating or promoting effect of the benzodiazepine tranquillizers diazepam, clorazepate, oxazepam and lorazepam.

Four benzodiazepine tranquillizers were tested for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. In comparison with the liver carcinogen, N-2-fluorenylacetamide, the benzodiazepines exhibited no initiating activity during a 14-week period of daily administration by gavage. To study the promoting activity, N-2-fluorenylacetamide was used to initiate altered foci and neoplastic nodules in rat liver during 8 weeks and then the benzodiazepines were administered by daily gavage for a period of 12 weeks. The liver tumor promoter phenobarbital had a substantial enhancing effect upon the persistence of nodules but none of the benzodiazepines showed a similar effect. Thus, in the process model systems used, to detect initiating or promoting potential effect, the benzodiazepine tranquillizers failed to exhibit either an initiating or a promoting action.

2-Acetylaminofluorene↗
PubMed1981

A toxicologic evaluation of ethyl fluclozepate (CM 6912).

This paper presents the results of acute, subacute, and chronic toxicity studies on ethyl fluclozepate (CM 9612). Acute toxicity was studied in rats and mice of both sexes by oral and intraperitoneal routes. This study established the very low toxicity of this compound. The LD0 by the oral route in these two species is at least higher than 4 g/kg, whereas by the intraperitoneal route the compound has a LD50 of 645 mg/kg at the lowest level. The 3- and 6-month subacute and chronic toxicity studies were carried out in baboons and in rats. The only effects observed during these studies were sedation in the baboon, a slight decrease of the heart rate also in baboons (6 months), and the presence of foam cells in rat lungs after only 6 months of treatment. The sedation and the decrease of heart rate are not toxic effects, but rather the consequence of the anxiolytic activity of CM 6912. Pulmonary foam cells occurred in rats only after a long period of treatment (6 months) and at very high dose levels. This lesion was considered evidence of pulmonary phospholipidosis, a change known to occur frequently with compounds of this nature.

Animals↗
PubMed1980

Genotoxicity of the antihypertensive drugs hydralazine and dihydralazine.

The genotoxicity of the antihypertensive agents hydralazine and dihydralazine was tested in mammalian cells and bacteria. Both drugs elicited DNA repair in rat hepatocyte primary cultures. In the Ames test, both with and without an S-9 fraction, hydralazine was mutagenic in strains TA100 and TA1537, whereas dihydralazine was weakly mutagenic in strain TA1537. These findings support the observation that hydralazine is carcinogenic in mice. The carcinogenicity of many chemicals results from interaction with DNA. Since these studies demonstrate that hydralazine and dihydralazine damage DNA in mammalian cells, these drugs should be viewed as potential human carcinogens.

Acetylation↗
PubMed1980

A medulloblastoma in a baboon (Papio papio).

A transitional medulloblastoma was found in the cerebellum of a young female baboon. The primary lesion that permitted its discovery was papillary and retinal edema in the peripapillary zone.

Animals↗
PubMedDate not supplied

Neurobehavioral effects of D-glaucine in rats.

Adult, male Fischer-344 rats were dosed by gavage with 75 or 150 mg/kg of D-glaucine for six weeks. A battery of neurobehavioral tests was given prior to dosing, after three and six weeks of dosing and three and five weeks after cessation of dosing. Routine histopathological assessment was made five weeks after cessation of exposure. Animals receiving the high dose of glaucine showed a transient decrease in body weight, decreased motor activity after three weeks of dosing, and decreased grip strength after three and six weeks of dosing. The lower dose of glaucine decreased forelimb grip strength after six weeks of dosing. Glaucine had no effects on other measures of motor function (negative geotaxis, hindlimb splay) or reactivity to noxious (hot plate, tail flick) or non-noxious stimuli (sound or air puff). By five weeks postdosing, the neurobehavioral functioning of glaucine-exposed rats was not different than controls. Histopathological examination revealed a brown discoloration of the thyroid, brain, and muscles and the appearance of brown pigments in the cell bodies of neurons located in the brain stem and spinal cord.

Acoustic Stimulation↗